Abstract
Visceral pain represents an unmet clinical need due to the lack of safe and generalizable therapies. Given the analgesic potential of music and the underlying crosstalk between auditory and nociceptive pathways, this study aims to delineate the neural circuits interfacing auditory processing and visceral pain modulation. Using a mouse model of early-life stress, we identify a cortico-cortical circuit linking the primary auditory cortex (Au1) to the anterior cingulate cortex (ACC) that mediates stress-induced visceral pain. Mechanistically, early-life stress suppresses the activity of Au1 inhibitory (GABAergic, Au1GABA) neurons, which disinhibits downstream ACC excitatory (glutamatergic, ACCGlu) neurons, thereby driving visceral hypersensitivity. Notably, music intervention alleviates visceral pain by restoring Au1GABA neuronal activity and suppressing ACCGlu activity. In conclusion, this study unveils the Au1-ACC circuit as a critical hub for stress-induced visceral hypersensitivity and music-induced analgesia, providing a mechanistic foundation for clinical translation of music therapy in visceral pain management.
Data availability
All the data generated in the current study are presented in the figures and supplementary materials. The relevant raw data are provided as a Source Data file. Source data are provided with this paper.
Code availability
Calcium responses were analysed using a custom MATLAB script provided by ThinkerTech (Nanjing, China). The script with detailed instructions can be downloaded from the repository below: https://github.com/mdp10yy/TrippleColorMultiChannel-Script.git.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (grant numbers: 82530041 and 32230041 to G.Y.X., 82571396 to Y.Y.), the National Key Research and Development Programme of China (2024YFC3505200 and 2024YFC3505203 to G.Y.X.), the Chinese Red Cross Foundation National Brain Nutrition Research Fund (to G.Y.X.) and the Natural Science Foundation of Jiangsu Province (BK20255001 to G.Y.X.). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Y.Y., W.Q.K. and Y.H.H. acquired and analysed the data, prepared the figures and manuscript. Q.Q.C., Y.C.L. and F.C.Z. interpreted the data. HDN revised the manuscript. G.Y.X. designed the experiments, supervised the experiments and finalized the manuscript. All authors read and approved the final manuscript.
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Yu, Y., Kuang, WQ., He, YH. et al. A primary auditory cortex-anterior cingulate cortex circuit underlying cross-modal visceral pain modulation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69135-3
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DOI: https://doi.org/10.1038/s41467-026-69135-3
